Cutaneous wound healing represents a highly coordinated process to achieve tissue homeostasis, which involves complex interactions of different types of resident cells and infiltrating immune cells as well as their secreted soluble mediators [23]. The repair process involves three distinct but overlapping phases: inflammation, tissue formation, and remodeling [23]. Upon tissue insult, the immediate inflammatory response is characterized by infiltration and activation of leukocytes, whereas a delayed or excessive inflammatory response may lead to abnormal wound healing in diabetic patients, scarring and fibrotic diseases. Aside from leukocytes which act as the principal cellular component of the early inflammatory response, macrophages contribute to all stages of wound repair [23-25]. Particularly, several studies have shown that M2 macrophages can produce mediators essential in the resolution of inflammation and tissue modeling, thus promoting wound repair [26, 27]. Recent studies have demonstrated that systemically injected MSCs can home to injury sites [28-30], differentiate into multiple types of skin cells [30, 31] and secrete various factors with proliferative, anti-inflammatory, angiogenic or chemotactic effects [30, 31], thus facilitating survival/proliferation of both resident and replacing cells, and consequently accelerating wound repair [31]. Although the role of macrophages [23-25] and MSCs [24, 28, 29] have been implicated in wound repair, little is known about their interactions, specifically whether MSCs can promote the transition of M1 to M2 macrophage in accelerating the healing of skin wounds.
Allergic contact dermatitis (ACD) is one of the most prevalent skin diseases worldwide with significant economic burden. Clinically, ACD is the manifestation of delayed-type contact hypersensitivity (CHS) in response to small-molecular, highly reactive contact allergens (haptens), and is characterized by redness, papules and vesicles, followed by scaling and dry skin at the contact local site (62, 63). The hapten-induced murine contact hypersensitivity (CHS) is widely used as a model for human ACD. Comparable to the pathophysiology of human ACD, the murine CHS model comprises three phases: the sensitization phase (also termed as the afferent or induction phase), the elicitation or challenge phase, and the resolution/regulation phase (62). The sensitization phase is initiated immediately after the first exposure of skin to haptens, followed by the uptake and process of haptens or haptenated proteins by the cutaneous antigen-presenting cells, particularly, the dendritic cells (DCs) (62). The haptenized or activated DCs migrate from skin to regional draining lymphnodes (dLNs) where they are responsible for the priming of allergen-specific T lymphocytes, including CD8+ cytotoxic and CD4+ T helper cells. Afterwards, the primed T cells re-circulate between lymphoid organs and skin (14). The elicitation phase occurs at the encounter of the same hapten, resulting in recruitment of blood leukocytes, amplified activation of allergen-specific effector CD8+ and CD4+ T cells, as well as activation of innate immune cells, particularly, mast cells. The activation of several subtypes of immune cells leads to enhanced production of an array of inflammatory cytokines and mediators that contribute to the appearance of eczematous lesions within 24-48 hours. The resolution/regulation phase occurs following the clearance of haptens from the skin contact site and the recruitment and activation of CD4+ Tregs and other potential regulatory immune cells, which subsequently leads to the resolution of all inflammatory processes (62). Currently, topical application of corticosteroid is the first-line palliative measure for ACD with short-term outcome, while allergen identification to improve contact avoidance is still challenging. Therefore, there is an urgent need to develop a more effective, curative desenstitizing tool based on specific cellular targets engaged by f multiple types of innate and adaptive immune cells in the complex but distinctively phased pathophysiological processes of ACD.